Cancer is a leading cause of death worldwide, and the development of effective therapies for cancer continues to be one of the most active areas of research and clinical development. Although a variety of innovative approaches to treat and prevent cancers have been proposed, many cancers continue to have a high rate of mortality and may be difficult to treat or relatively unresponsive to conventional therapies.
A large number of human carcinomas and hematologic malignancies are characterized, at least in part, by aberrant overexpression of a protein known as mucin-1 (MUC1) whose normal function is to help protect epithelial cells from toxins, microorganisms and other types of external environment stresses (Kufe et al., Hybridoma 1984; 3:223-32). MUC1 is a heterodimeric protein formed from the noncovalent interaction of two subunits which are encoded by a single transcript and then processed into subunits post-translationally, known as MUC1-N and MUC1-C. MUC1 is normally found at the apical borders of secretory epithelial cells, and when the cells lose polarity in response to stress, a reversible process for normal cells, MUC1 can interact with molecules that usually localize at the basolateral borders. In addition, in response to stress environments, the MUC1-N subunit, a large protein containing a variable number of tandem repeats (VNTR) that are extensively glycosylated with O-linked glycans, can be shed. The other subunit of MUC1, known as MUC1-C, has an extracellular domain, a transmembrane domain and a cytoplasmic tail, and can bind to a ligand that is responsible for physically associating MUC1 with the epidermal growth factor receptor (EGFR) (Li et al., J Biol Chem 2001; 276:35239-42; Schroeder et al., J Biol Chem 2001; 276:13057-64) as well as other receptor tyrosine kinases, such as ErbB2-4,20 FGFR321 and PDGFR (Li et al., Mol Cancer Res 2003; 1:765-75; Ren et al., Mol Cancer Res 2006; 4:873-83; Singh et al., Cancer Res 2007; 67:5201-10). In addition, MUC1-C has been associated with a variety of signaling pathways that include ErbB receptors, c-Src, β-catenin, transcription factors (p53, ERa) and other effectors, such as Grb2/SOS (Pandey et al., Cancer Res 1995; 55:4000-3; Kinlough et al., J Biol Chem 2004; 279:53071-7).
In transformed epithelial cells, membrane polarity is irreversible and MUC1 expression is upregulated over the entire surface of carcinoma cells (Kufe et al., 1984, supra). MUC1 overexpression is associated with decreased MUC1-N O-glycosylation, and the high levels of MUC1-N at the cell surface steric ally block cell-cell and cell-extracellular matrix interactions, which are associated with the malignant phenotype (Ligtenberg et al., Cancer Res 1992; 52:223-32; van de Wiel-van Kemenade et al., J Immunol 1993; 151:767-76; Wesseling et al., Mol Biol Cell 1996; 7:565-77). The MUC1-C subunit is now considered to be an oncoprotein, based on its involvement in diverse signaling pathways associated with tumorigenesis, and its overexpression has been shown to be involved in blocking induction of apoptosis in the response to DNA damage (Ren et al., Cancer Cell 2004; 5:163-75; Raina et al., J Biol Chem 2004; 279:20607-12), oxidative stress (Yin and Kufe, J Biol Chem 2003; 278:35458-64; Yin et al., J Biol Chem 2004; 279:45721-7), and hypoxia (Yin et al., J Biol Chem 2007; 282:257-66), as well as conferring anchorage-independent growth and tumorigenicity (Li et al., Oncogene 2003; 22:6107-10; Huang et al., Cancer Biol Ther 2003; 2:702-6; Huang et al., Cancer Res 2005; 65:10413-22; Schroeder et al., Oncogene 2004; 23:5739-47).
As discussed above, data from various laboratories indicate that the MUC1-N (α subunit) plays a role in cancer by conferring cellular properties that allow immune evasion and potentially metastatic spread. The MUC1-C (β subunit) engages signaling pathways responsible for tumor initiation and progression. These dual functions of MUC1 may explain the differing roles this antigen appears to play in different cancer indications. For example, MUC1 appears to be an early marker in cancers such as breast cancer and colon cancer (e.g., see Kretschmer et al., Mol Cancer. 2011 Feb. 11; 10(1):15; Mukhopadhyay et al., Biochim Biophys Acta. 2011 April; 1815(2):224-40; Saeki et al., Gastroenterology. 2011 March; 140(3):892-902), while MUC1 is associated with epithelial-mesenchymal transition (EMT) pathways and metastatic spread in cancers such as pancreas cancer and esophageal cancer (e.g., see Xu et al., Life Sci. 2011 Jun. 6; 88(23-24):1063-9; Besmer et al., Cancer Res. 2011 Jul. 1; 71(13):4432-42; Roy et al., Oncogene 2011 Mar. 24; 30(12):1449-59; Ye et al., Lab Invest. 2011 May; 91(5):778-87), and prevents terminal differentiation by reactive oxygen species in acute myeloid leukemia (AML) (e.g., see Yin et al., Blood. 2011 May 5; 117(18):4863-70; Fatrai et al., Exp Hematol. 2008 October; 36(10):1254-65), thereby allowing unlimited self renewal of these cancer cells.
Given the apparent role of MUC1 in the malignant phenotype of cancer cells, MUC1, and particularly MUC1-N, has been the focus of anti-cancer therapeutic approaches. Indeed, the majority of therapeutic approaches have targeted MUC1-N, the extracellular portion of the MUC1 heterodimer. However, such approaches targeting MUC1-N have not been successful in the clinic so far, possibly due to interference from MUC1-N that is shed from the cells. More recent studies have proposed targeting the MUC1-C subunit with antibodies against the extracellular domain, or with peptides, peptides conjugated with a carbohydrate polymer, small molecules, with preparations of tumor cells expressing MUC1, and with dendritic cell/tumor cell fusions. However, there are presently no approved cancer therapies that specifically target MUC1. Accordingly, there remains a need in the art for new products that effectively treat and/or prevent cancers associated with MUC1 expression or overexpression.